**5. Discussion**

The clinical assessment and managemen<sup>t</sup> of infertile men with azoospermia should consider the (i) differential diagnosis of azoospermia, (ii) identification of patients eligible for reconstructive procedures (e.g., OA), gonadotropin therapy (e.g., NOA-HH), or sperm retrieval, (iii) identification of patients with NOA-STF that might benefit from interventions (e.g., varicocele repair, hormonal modulation) before a sperm retrieval attempt, (iv) use of an optimal surgical method to harvest sperm, and (v) utilization of state-of-the-art IVF techniques when applicable. A detailed discussion of these aspects is outside the scope of this article and can be found elsewhere [5,9,10].

Nevertheless, the most challenging azoospermic patient to manage clinically is probably that with NOA-STF. Table 2 outlines the essential aspects to be considered under this scenario. Among several critical factors, a sensitive matter relates to hormonal modulation for men with NOA, as briefly described in clinical cases 1 and 2. The reason stems from the fact that it is generally believed that empirical medical treatment for men with NOA-STF is ineffective because gonadotropins' plasma levels are usually high. Yet, many patients with NOA-STF present with hypogonadism and might thus lack adequate levels of intratesticular testosterone, which are essential for spermatogenesis in combination with adequate Sertoli cell stimulation by FSH [80–82]. Furthermore, gonadotropin action is determined by the frequency, amplitude, and duration of its secretory pulses. Due to the high baseline levels of endogenous gonadotropins commonly seen in patient with NOA-STF, the relative amplitudes of FSH and LH are low, leading to a paradoxically weak stimulation of Leydig and Sertoli cells [35,83]. Therefore, there may be a potential role for pharmacotherapy in men with NOA [84,85].

**Table 2.** Interventions and recommended actions in the clinical managemen<sup>t</sup> of azoospermic men with nonobstructive azoospermia seeking fertility.



**Table 2.** *Cont.*

EAA: European Association of Andrology; EMQN: European Molecular Genetics Quality Network; AZF: azoospermia factor; FSH: Follicle-stimulating hormone; ICSI: intracytoplasmic sperm injection; LH: luteinizing hormone; micro-TESE: microdissection testicular sperm extraction; NOA-STF: nonobstructive azoospermia due to spermatogenic failure; PCR: polymerase chain reaction; SR: sperm retrieval; T/E: testosterone to estradiol ratio; TESE: testicular sperm extraction; TT: total testosterone; YCMD: Y-chromosome microdeletions. Adapted from Esteves [5], Asian J. Androl. 17, 459–470, 2015, an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License.

> Selective estrogen receptor modulators, aromatase inhibitors, human chorionic gonadotropin (hCG), and FSH have been used off-label to manipulate male reproductive hormones and optimize intratesticular testosterone production [5,84,86–88]. The goals are to induce recovery of sperm to the ejaculate or improve surgical sperm retrieval rates. Case series and a few cohort studies suggested that these treatments might increase sperm retrieval rates, and in some cases, treatment was associated with the return of minimal numbers of sperm to the ejaculate [5,84–88]. Despite that, no randomized controlled trial exists, making it difficult to make clear recommendations on this matter.

> Notwithstanding these observations, limited data indicate that treatment with hCG and recombinant FSH could lead to 10–15% higher sperm retrieval rates than sperm retrieval with no previous treatment [35]. Furthermore, hCG treatment was shown to improve intratesticular testosterone production remarkably in men with NOA [89]. Based on these concepts and with the goals of inducing return of sperm to the ejaculate or improving surgical sperm retrieval rates, we have used hCG alone or in combination with recombinant FSH off-label to optimize intratesticular testosterone production and FSH action, as previously described [5]. Our treatment protocol, utilized in clinical cases 1 and 2, relies primarily on hCG to boost intratesticular production. Additionally, hCG

treatment was shown to decrease FSH levels, which are typically elevated in most of these patients [51]. Based on limited data from animal and human studies, it has been speculated that FSH reset to normal levels might reduce Sertoli cell desensitization caused by excessive circulating endogenous gonadotropins [90–95]. Consequently, an increased Sertoli cell function and expression of FSH receptors could be obtained. Our patients are followed with a monthly hormonal assessment, and we add an aromatase inhibitor in the course of treatment when the testosterone (ng/dL) to estradiol (pg/mL) ratio becomes less than 10. We also prescribe recombinant FSH when, after hCG treatment, the FSH levels drop below 1.5 IU/L [4,51]. The ultimate goal is to increase intratesticular testosterone to optimal levels through hCG stimulation while securing adequate FSH levels within normal ranges. Although we need more data in this area, hormone stimulation for men with NOA may be worth considering in selected cases.
